CEREBRAL VASOSPASM AND RESOLUTioN WITH NICARDIPINE IN RABBITS

Recai Tuncer M.D.

Department of Neurosurgery. School of Medicine. Akdeniz University. Kepez. Antalya. TURKiYE

Turkish Neurosurgery 2 : 14-18 1991

SUMMARY:

The effects ofNicardipine. a Ca++ channel blocker. on vasoconstriction of rabbit basilar artery in two differentconditions. one with a dot contacting the wall of the artery and the other without. were investigated in thisstudy. The Initial diameters of the basilar arteries were measured in all groups. When intradsternal blood wasapplied. They were found to be 0.}5+0.09 mm in the dotremovalgroup (CR).0.34+0.13 mm in the dot + Nicar­dipine group (C+N) and 0.}1+0.07 mm in the dot removal + Nicardipine group (CR+N). Each group showedsignificant difference when compared with the initial diameter (P<O.OOI).Mean basilar artery diameter was0.4+0.08 mm following CR, 0.52+0.10 mm following C+N and no significant difference was found betweenthese two conditions and their dot contact conditions. It was 0.79+0.10 mm in the CR+N group and this wasfound to be statistically significant when compared with to dot contact cnodition (P<0.001). Therefore. to ob­tain optimal benefit in subarachnoid haemorrhage the mechanical removal of the dot. even a limited amount.and administration of Nicardipine might be useful.

KEYWORDS

Nicardipine. Rabbit. Vasospasm.

INTRODUCTION

The pathogenesis of cerebral vasospasm which af­fects the mortality and morbidity of subarachnoidhemorrhage (SAH)is not clear (4,6.7,17.25.26.31)butit is considered to be multifactorial (24.37.39.45).AfterSAH. endothelial damage and release impairment ofendothelium· derived relaxing factor (EDRF)and alsovasoconstrictor substances from the blood in the

subarachnoid space are all claimed to play an impor'tant role in vasospasm (1.2,10,12,13,15,18.22.24,25,27.29.32.39.42.44).It is thought that these substancesproduce vasoconstriction by increasing the transmem­brane influx of Ca++ (3,11.19.35.38.41).Further. in­flammation is also thought to producevasoconstriction (6,17,23.36).

Since the etiopathogenesis of cerebral vasospasmis not known. treatment is controversial. A number

of studies on this subject are evidence of this. Thecommonest methods include clot removal

(16,28.33.42), hypervolemia and hypertension (39).cerebral protection for ischaemia (31).suppression ofplatelet aggregation. modification of prostaglandinsynthesis (6,13).inhibition ofTXA2 synthesis and/orstimulation of prostacyclin synthesis (9,13,14.31)andtopical. intrathecal or intravenous Ca+ + channelblockers (5.8,19.34.35.38.41).

Nicardipine is a Ca+ + channel blocker. It protectsneural functions by decreasing Ca++ influx in-

14

tracellularly and has important vasodilatory effects(3,11.15.40).

The purpose of this study is to investigate the ef­fects of Nicardipine on vasoconstriction of the basilarartery in rabbits, under two different conditions, onewith the clot contacting the wall of the artery and theother not.

MATERIAL AND METHODS

Twenty-eight albino New-Zealand rabbits.weighing from 2.0 to 3.5 kg each. were used for theexperiment. Anesthesia was obtained with 1.5 g/kgUrethan intraperitoneally. Following anesthesia theear vein and femoral artery were catheterised and theartearial blood pressure via the femoral artery wasmonitored with a polygraph (NECSan-ei instrumentsLtd., Tokyo-Japan) and blood was withdrawn tomeasure arterial PaC02 and pH. Tracheostomy wasdone with an indsion from the mandible to the

jugular fossa. The trachea and oesophagus wereretracted with a self-retaining retractor and the clivuswas exposed via stripping off the musches. The clivuswas removed with a dental drill and the dstern con­

taining the basilar artery and its branches was expos­ed. The dura mater was indsed and exdsed under

a surgical microscope (AD Sdentific Instruments, Buf·falo. New-York). The animals were divided into fourgroups. The first was the control group (n=6). 0.5 mlnonheparinised autologous blood was administered

intradsternally for 15 minutes in all groups andvasoconstriction of the basilar artery was obtained.In the second group (n=6) the dot was removed andthe area was washed with saline solution and left for

60-90 minutes. In the third group (n=8) nicardipineHCI (0.01mglml) (Sandoz. 4. Levent, Istanbul) was ap­plied on the dot for 15-20minutes. In the fourth group(n=8), the dot was removed and nicardipine HCI (0.01mg/ml) was applied for 15-20 minutes.Microphotographs were taken at the beginningin all groups, and at the end of each step in groupsother than the control group.

The measurements of PaC02 and pH were donewith the autoanalyzer (Stat Profile Analyzer. NovaBiomedical-Waltham. Massachusetts). In order to findthe changes in arterial diameters a measurement wasmade with to formula: Arterial diameter measured

on photographs in mm/Magnification degree of themicroskope.

Student's t-test was used for statistical analysis.

RESULTS

The physiological parameters of the experimen­tal group are shown in Table 1. The mean basilarartery was found to be 0.82 mm in the control group.No significant difference was found between the in­itial arterial diameters of all groups. In the 2nd, 3rdand 4th groups to which intradsternal blood was ap­plied, the mean artery diameters were determinedas 0.32+0.09 mm. 0.34+0.13 mm and 0.31+0.07 mm

respectively. A significant degree of vaso-contrictionwas found when each was compared with their in­itial diameter and the control group (p<0.001).

Mean artery diameter was 0.41+0.08 mm after dotremoval and there was no significant difference whencompared with dot presence (Fig 1).It was 0.52+0.10mm in the dot+Nicardipine group and moderatevasodilatation was determined when compared withdot presence. but no significant difference was found(Fig 2).

Fig 1 : Microphotographic representation of basiler artery in the clot removal group. a) No intracisternal blood. b) 15 minutes after intra­cisternal blood clot. c) 90 minutes after clotremoval.

Mean artery diameter was 0.79+0.10 mm in theclot removal+Nicardipine group. significantvasodilatation was found when compared with dotpresence (P<0.001) (Fig 3)

Mean arterial diameters of all groups are showngraphically in (Fig 4).

15

Fig 2 : a) Microphotographic representation of basilar artery in theclot+Nicardipine group. a) No intracisternal blood.

Fig 2: c) 15 minutes after clot+Nicardipine.

Fig 3: b) 15 minutes after intracisternal blood dot.

16

Fig 2: b) 15 minutes after intracisternal blood clot.

Fig 3 : b) Microphotographic representation of basilar artery in theclot removal +Nicardipine group.

Fig 3 : c) 15 minutes after dot removal+Nicardipine.

Mean Arterial Diameters (mm)

In experimental studies, in general vasospasm isproduced with autologous blood application in­taasternally. Blood is either put into the asternsurgically (6,9.11,14,16.17,22) or via injection andcatheretisation (1.3 .4.5 .18.26). In this studyvasoconstriction was obtained after introduction of

autologous blood into the astern. After clot removal.an increase in the diameter of the basilar artery wasdetermined, but it was not significant. Some authorsclaimed that clot removal in the first 24-48 hours

might prevent chronic vasospasm (16.28.33.42). In­agawa suggested that this improvement in vasospasmwas not of a significant degree and in addition.multifactorial effects were required (20.21). On thecontrary, Ohta wrote that early clot removal had therisk of severe brain aedema and bleeding due toretraction and was not effective in the prevention ofvasospasm (30). Wakayabashi reported that severevasospasm developed on the side opposite to theoperative approach in patients with the pterional ap­proach (44).

After administration of Nicardipine without clotremoval. some improvement was observed invasospasm. but it was not enough. This might be dueto dense clot presence in the space. But after SAH.the blood does not always show diffuse distributionin the subarachnoid space, it may be local and dense.Lewis reported that intrathecal Nicardipine ad­ministration did not produce any significant benefit(23).It was considered that blood clots on the adven­titial surface might cause a disturbance of vessel wallnutrition and the vessel wall penetration of in­trathecally administered compound might be im­paired in a similar manner.

Extensive influx of Ca+ + into the smooth mus-

I-INITIAL DIAMETER C-ClOT PRESENCE

MABP (mmHg) PaC02 (mmHg)PH

Control

87+434.2+0.47.38+2.91

Clot removal

85+437.0+2.47.40+3.21

Clot + Nicardipine

79+236.6+ 1.87.39+ 3.60

Clot removal + Nicardipine

79+537.2+1.07.40+0,02

(MABP : Mean arterial blood pressure. PaCO, Arterial partial

pressure of carbon dioxide, mean+SEM)Tablo 2 : Mean arterial diameters (mean+SEM)(mm)No Intracis-

Intracister-After

Temal blood

nal bloodprocedure

Control

0.82+017

(0.58-1.00)Clot

0.79+0.100.32+0.090.41+0.Q7

removal(0.56-1.00)(0.20-0.45)(0.35-0.55)

Clot +

0.80+0.120.34+0.130.52+0.10

Nicardipine

(0.62-0.84)(0.17-0.50)(0.34.-0.63)

Clot removal +

0,83+0.1320.31+0.070.79+0.10

Nicardipine

(0.63-0.95)(0.22-0.44)(0.62-0.91)

17

cle cells of the cerebral vessels produce vasoconstric­tion (8.12). Nicardipine, a Ca+ + channel blocker,hinders this influx. thus the contractile activity dueto Ca++ and ischemia might be prevented (3.39). Inaddition, the direct relaxation effect of nicardipineon smooth muscles and inhibition of platelet aggrega­tion has been shown (15.40). Following nicardipineadministration after clot removal. there was signifi­cant resolution in vasospasm in this study. Ohmanand Heiskanen reported that early surgical interven­tion in association with Ca+ + channel blockers had

given excellent results(34).

In consclusion. although the etiopathogenesis isstill unclear, it seems that vasodilatatory agents willcontinue to be used for the resolution of vasospasmof the cerebral arteries which tend to respond withvasocostriction, when they meet blood, Our resultsshowed that administration of Ca+ + channel

blockers could produce limited benefit when a clotwas present, but administration of Ca++ channelblockers following clot removal could resolve thevasospasm. Therefore after SAH, administration ofCa+ + channel blockers seems to have a more

benefiaal effect on the resolution of vasospasm whenused in assoaation with the removal of as much of

the clot as possible.

Table 1 : Physiological parameters

I C CR.N

O.8Stil.1S

I C C.N

Groups

".tI~O.'2

C CR

O.7ltow

DISCUSSION

mm1

o

04

02

06

06

Fig 4: Mean arterial diameters.

Correspondence: Y. Doc. Dr. Recai TuncerAkdeniz Universitesi. Tip FakiiltesiNorosirurji Anabilim Dali. Kepez. Antalya.

REFERENCES

I. Alksne JF. and Smith RW: Experimental models of spasm. ClinNeurosurg 24:216-227. 1977.

2. Alksne JF. and Branson J: Pathogenesis of cerebral vasospasmNeurological Research 2:273-282. 1980.

3. Baena RRY.Gaetani P. Marzatico F. et al: Effects of nicardipineon the ex vivo release of eicosanoids after experimentalsubarachnoid hemorrhage. J Neurosurg 71:903-908. 1989.

4. Barry KJ. Gogjian MA. and Stein BM: Small animal model forinvestigation of subarachnoid hemorrhage and cerebralvasospasm. Stroke 10(5):538-541. 1979.

5. Brandt L. Anderson KE. Bengtsson B.et al: Effects of nifedipineon pial arteriolar calibre: an in vivo study. Surg Neurol12:349-352. 1979.

6. Chyatte D. Rusch N. Sundt T: Prevention of chronic experimentalcerebral vasospasm with ibuprofen and high dose methlpred­nisolon. J Neurosurg 59:925-932. 1983.

7. Delgado TJ. Arbab MA. Warberg J. Svendgaard N: The role ofvasopressin in acute vasospasm. J Neurosurg 68:266-273.1988.

8: Edvinsson L. Brandt L. Andersson KE: Effect of a caldum an­

tagonist on experimental constriction of human brain vessel.Surg Neurol11:327-330. 1979.

9. Egemen N. Birler K. Avrnan N. Turker RK:Experimental cerebralvasospasm: Resolution by ilioprost. Acta Neurochir 131-34.1988.

10. Findlay JM. Weir BKA. Steinke D. et al: Effect of intrathecalthrombolytic therapy on subarachnoid clot and chronicvasospasm in a primate model of SHA. J Neurosurg 69:732-735.1988.

11. Flamm ES. Adams HP. Beck DW. et al: Dose-escalation studyof intravenous nicardipine in patients with aneurysmalsubarachnoid hemorrhage. J Neurosurg 68:393-400. 1988.

12. Fujiwara S. Kassel NF. Sasaki T. et al: Selective hemoglobin in­hibition of endothelium-dependent vasodilatation of rabbitbasilar artery. J Neurosurg 64:445-452. 1986.

13. Fukumori T. Tani E. Maeda Y. and Sukenaga A: Effect of pro­stacycllin and indomethadn on experimental delayed cerebralvasospasm. J Neurosurg 59:829-834. 1983.

14. Hadyakupoglu S. Kaya M. Cetinalp E. Yucesoy A: Effects of pro­stacyclin and adenosin triphosphate on vasospasm of caninebasilar artery. Surg Neurol 24:126-140. 1985.

15. Handa. T. Yoneda A. Koyama T: Experimental cerebralvasospasm in cats: Modification by a new syntheticvasodilatator YC-93. Surg Neurol 3:195-199. 1975.

16. Handa Y. Weir BKA.Nosko M. et al: The effect of timing of clotremoval on chronic vasospasm in a primate model. J Neurosurg67:558-564. 1987.

17. Heros RC, Zervas NT. Negoro M: Cerebral vasospasm. SurgNeurol 5:354-362. 1976.

18. Hongo K. Kassell NF. Nakagomi T. et al: Subarachnoid hemor­rhage inhibition of endothelium-derived relaxing factor in rab­bit basilar artery. J Neurosurg 69:247-253. 1988.

19. Hollerhage H. Gaab MR. Zumkeller M. and Walter GF: The in­fluence of nimodipine on cerebral blood flow autoregulation andblood-brain barrier. J Neurosurg 69:919-922. 1988.

20. Inagawa T. Yamamoto M. and Kamiya K:Effect of clot removalon cerebral vasospasm. J Neurosurg 72:224-230. 1990.

2I. lnagawa T: Effect of early operation on cerebral vasospasm. SurgNeurol 33:239-246. 1990.

22. Kanamaru K. Weir BKA. Findlay JM. et al: Pharmacologicalstudies on relaxation of spastic primate cerebral arteries insubarachnoid hemorrhage. J Neurosurg 71:909-915. 1989.

18

23. Lewis PJ. Weir BKA.Nosko MG. et al: Intrathecal nimodipinetherapy in a primate model of chronic cerebral vasospasm.Neurosurgery 22(3):492-500. 1988.

24. Nakagomi T. Kassell NF. Sasaki T. et aI: Effect of subarachnoidhemorrhage on endothelium-dependent vasodilatation. JNeurosurg 66:915-923. 1987.

25. Nakagomi T. Kassell NF. Sasaki T. et al: Effect of removal of theendothelium on vasocontraction in canine and rabbit basilar

arteries. J Neurosurg 68:757-766 1988.26. Nakagomi T. Kassell NF. Sasaki T. et al: Etiology of the dist rup­

tion in blood-arteriel wall barrier following experimentalsubarachnoid hemorrhage. Surg Neurol 34:16-28. 1990.

27. Newell DW. Eskridge JM. Mayberg MR. et al: Angioplasty forthe treatment of symptomatic vasospasm followingsubarachnoid hemorrhage. J Neurosurg 71:654-660. 1989.

28. Nosko M. Weir BKA.Lunt A. et aI: Effect of clot removal at 24

hours on chronic vasospasm after SAH in the primate model.J Neurosurg 66:416-422. 1987.

29. Nozaki K. Uemura Y. okamoto s. et al: Relaxant effect of

caldtonin gene-related peptide on cerebral arterial spasm induc­ed by experimental subarachnoid hemorrhage in dogs. JNeurosurg 71:558-564. 1989.

30. Ohta H. Ito Z. Yasui N. Suzuki A: Extensive evacuation of

subarachnoid clot for prevention of vasospasm-effective or not.Acta Neurochir 63:111-116. 1982.

31. Otha T. Kikuchi H. Hasmi K. Kudo K: Nizofenone administra­

tion in the acute stage following subarachnoid hemorrhage:Results of a multicenter controlled double blind clinical study.J Neurosurg 64:4120-426. 1986.

32. okamoto S. Handa H. Handa Y:Hemolysate-induced release ofprostaglandin like substances from the canine cerebral arteries.Surg Neurol 23:421-424. 1985.

33. Osaka K:Prolonged vasospasm produced by the breakdown pro­ducts of erythrocytes. J Neurosurg 47:403-411. 1977.

34. Ohman J. Heiskanen 0: Effect of nifedipine on the outcome ofpatients after aneurysmal subarachnoid hemorrhage andsurgery J Neurosurg 69:683-686. 1988.

35. Peroutha SJ. Ailen GS: Calcuim channel binding sites labelledby H-nimodipine in human brain. J Neurosurg 59:933-37.1983.

36. Peterson JW. Kwun B. Hackett JD. Zervas NT: The role of in­flammation in experimental cerebral vasospasm. J Neurosurg72:767-774. 1990.

37. Peterson JW. Rousson L. Kwun B. et al: Evidence of the role ofhemolysis in experimental cerebral vasospasm. J Neurosurg72:775-781. 1990.

38. Petruk Kc' West M. Mohr G. et aI:Nimodipine treatment in poorgrade aneurysm patients: Results of a multicenter doubleblindplacebo controlled trial. J Neurosurg 68:505-517. 1988.

39. Sano K: Cerebral vasospasm and aneurysm surgery. In sano K.ed. clinical Neurosurgery. Baltimore. Williams-Wilkins. p:13-58.1983.

40 .Sorkin EM. Clissold SP:Nicardipine: A review. Drugs. 33:296-345.1987.

41. Stulken EH. Johston WE. Prough DS. et al: Implication ofnimodipine prophylaxis of cerebral vasospasm an anestheticmanagement during intrathecal aneurysm clipping. J Neurosurg62:200-205. 1985.

42. Suzuki J. Onuma T. Yoshimoto T: Results of early operationson cerebral aneurysms. Surg Neurol 11:407-412. 1979.

43. Tsukahara T. Hongo K. Kassel NF. Ogawa H: The influence ofexperimental subarachnoid hemorrhage on the relation in duc­ed by vasoactive intestinal ploypeptide in the cerebral arteriesof the rabbit. Neurosurgery 24(5):731-734. 1989.

44. Wakabayashi T. Fujita S: Removal of subarachnoid blood clotafter subarachnoid hemorrhage. Surg NeuroI21:553-556. 1984.

45. Walker V. Pickard JD. Smythe P. et al: Effects of subarachnoidhemorrhage on intracranial prostaglandins. J Neurol NeurosurgPsychiat 46:119-125. 1983.